In summary, we have developed BBB‐permeable and glioma and CLN‐homing CpG nano‐immunoadjuvant (t‐NanoCpG) that enables intravenous and intranasal administration to strongly stimulate the maturation of dendritic cells and production of proinflammatory cytokines in vivo and to reprogram tumor immune microenvironment by enriching ICD, activated APCs and CD8+ T cells. The gene discussed is CD8A; the disease is glioma.